Urotensin-II (U-II) is a cyclic neuropeptide with potent cardiovascular effects. Originally isolated from the caudal neurosecretory system of teleost fish, the primary structure of U-II has been established for several species of vertebrates, including various fish species, frogs, and humans. Sequence analysis of various U-II peptides from different species has revealed that, while the N-terminal region is highly variable, the C-terminal cyclic region of U-II is strongly conserved. Indeed, this cyclic region, which is responsible for the biological activity of U-II, is fully conserved from fish to humans (Coulouran, et al., Proc. Natl. Acad. Sci. USA (physiology), 95:15803-15808 (1998)). The fact that evolutionary pressure has acted to fully conserve the biologically active sequence of U-II suggests that this polypeptide plays an important role in human physiology.
The cyclic region of U-U includes six amino acid residues (-Cys-Phe-Trp-Lys-Tyr-Cys-(SEQ ID NO: 1)) and is structurally similar to the biologically important central region of somatostatin-14 (-Phe-Trp-Lys-Thr-(SEQ ID NO: 2)). However, molecular cloning and sequence analysis of the carp preprourotensin II gene suggests that U-II and somatostatin are not derived from a common ancestor (Ohsako, S., et al., J. Neurosci., 6:2730-2735 (1986)).
In fish, U-II peptides have been shown to exhibit several activities, including general smooth muscle contracting activity, although responses vary between species and vascular beds (Davenport, A., and Maquire, J., Trends in Pharmacological Sciences, 21:80-82 (2000); Bern, H. A., et al., Recent Prog. Horm. Res., 45:533-552 (1995)). Fish U-II has also been shown to possess constrictor activity in mammals, including major arteries in rats, but the receptor(s) mediating these peptide actions are not fully characterized.
Recent studies have reported that an orphan human G-protein-coupled receptor, homologous to the rat GPR14 and expressed predominantly in cardiovascular tissue, functions as an U-II receptor (Ames, H., et al., Nature, 401:282-286 (1999)). Fish (goby) and human U-II reportedly bind to recombinant human GPR14 with high affinity, and the binding is functionally coupled to calcium mobilization. Human U-II is found within both vascular and cardiac tissue (including coronary atheroma) and effectively constricts isolated arteries from non-human primates (Ames, H., et al., supra). The potency of vasoconstriction of U-II is substantially greater than that of endothelin-1, making human U-II one of most potent mammalian vasoconstrictors currently known. In vivo, human U-II markedly increases total peripheral resistance in anaesthetized non-human primates, a response associated with profound cardiac contractile dysfunction (Ames, H., et al., supra).
Since human U-II-like immunoreactivity is found within cardiac and vascular tissue (including coronary atheroma), U-II is believed to influence cardiovascular homeostasis and pathology (e.g., ischemic heart disease and congestive heart failure). Furthermore, the detection of U-II immunoreactivity within spinal cord and endocrine tissues suggests that U-II may have additional activities, including modulation of central nervous system and endocrine function in humans (Ames, H., et al., supra). Indeed, a number of maladies have been potentially linked to an excess or an under expression of U-II activity, including ischemic heart failure, hypotension, portal hypertension, angina pectoris, variceal bleeding, myocardial infarction, ulcers, and certain psychological and neurological disorders. Thus, there is a strong need for the development of potent compounds capable of modulating U-II activity, including U-II inhibitors or antagonists.